AEB071

A selective protein kinase C (PKC) inhibitor

• PKC is an important mediator of B-cell receptor (BCR)-NF-?B activation as it phosphorylates CARD11 of the CARD11-Bcl10-MALT1 (CBM) signaling complex. The CBM complex then activates the I kappa B kinase (IKK) complex, leading to the translocation of NF-?B to the nucleus and expression of its target genes.³¹ Isoforms of PKC have been shown to play a key role in cellular signaling, proliferation, differentiation, migration, and apoptosis.⁹⁵
• Two Ga proteins, GNAQ and GNA11, are constitutively activated in the majority of blue nevi and melanomas of the uvea.⁹⁶ GPCRs are increasingly recognized for their role in stimulating growth and malignant transformation, and the signaling from these receptors is often mediated by PKC.⁹⁷
• In vivo, mutant GNAQ and GNA11 transform melanocytes and induce rapid tumor growth in mice when introduced into immortalized murine melanocytes.^96,98 Uveal melanoma cell lines with these mutations are sensitive to PKC inhibitors.^96,98
• AEB071 is an orally bioavailable, novel pan-PKC inhibitor.⁹⁵
• Two Phase I studies using AEB071 are underway. The first is in patients with CD79-mutant DLBCL and the second in patients with metastatic uveal melanoma.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

MEK162
(ARRY-162)

Targets the RAS-RAF-MEK-ERK pathway by strong and selective MEK inhibition

• Mitogen-activated ERK kinases 1 and 2 (MEK1 and MEK2) play important roles in cancer cell proliferation, apoptosis, and metastasis. MEK1 and MEK2 are key components of the RAS-RAF-MEK-ERK signaling pathway.^1,2
• Defects in the RAS-RAF-MEK-ERK signaling pathway are closely associated with the development of human tumors, such as melanoma, pancreatic, colon, lung, and thyroid cancers.¹
• K-RAS and B-RAF mutations increase the sensitivity of tumor cells to MEK inhibitors.^1,2
• MEK162^* is an oral, highly selective MEK inhibitor.² In preclinical studies, MEK162 showed significant antitumor activities in cell lines and animal models.^1,2
• MEK162 is currently being investigated as single agent and in combination with other targeted agents in several Phase Ib and Phase II trials in advanced solid tumors, such as malignant melanoma, colorectal cancer (CRC), and biliary tract cancer (BTC).

MEK162 is licensed from Array BioPharma Inc.

*MEK162 (also known as ARRY-162) is licensed from Array BioPharma Inc.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LGX818

An oral, highly selective RAF kinase inhibitor

• The RAF protein is a key component of mitogen-activated protein kinase (MAPK) signal transduction pathway, which controls proliferation, differentiation, and apoptosis in mammalian cells through RAS, RAF, and extracellular-signal-regulated kinase (ERK) kinase (MEK).³
• There are three isoforms of RAF: A-RAF, B-RAF, and C-RAF.3 Activating mutations of B-RAF have been identified in multiple cancers, most notably in melanomas but also in colorectal cancer, serous borderline ovarian cancer, and papillary thyroid carcinomas.^3,35 The most common B-RAF mutation is V600E which accounts for 90% of all cancer causing B-RAF mutations.^35,36
• Selective RAF inhibitors have demonstrated significant efficacy in patients with tumors harboring the B-RAF^V600E mutation.³⁶
• LGX818 is small molecule selective RAF kinase inhibitor, with the unique characteristic of binding to B-RAF^V600E. The compound therefore suppresses the RAF-MEK-ERK pathway in tumor cells expressing B-RAF^V600E but does not evoke antiproliferative activity in wild-type B-RAF tumor cells.³⁷
• Preclinical studies have shown excellent pharmacology and toxicology profiles for LGX818. LGX818 has demonstrated favorable efficacy in B-RAF^V600E human melanoma xenograft models.³⁷ In mouse/rat xenograft models expressing B-RAF^V600E LGX818 induces tumor regression at low doses. Importantly, LGX818 shows a 50-fold increase in potency compared with other RAF inhibitors.³⁷
• Overall, LGX818 is well tolerated and has shown an excellent safety profile in mouse/rat xenograft and other in vivo studies.³⁷
• A Phase I study using oral LGX818 in advanced or metastatic melanoma patients harboring B-RAF V600 mutations is under way.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

DOVITINIB
(TKI258)

BGJ398

FGFR inhibitors

• Activating mutations or overexpression of FGFRs or their ligands have been associated with neoplastic progression and tumor vascularization in multiple cancer types, including breast cancer, bladder cancer, multiple myeloma (MM), hepatocellular, and renal cell carcinoma.^38-42
• Aberrant activation of FGFR signaling has been shown to result in poor patient prognosis. In a recent analysis of 880 unselected breast carcinomas, amplification of FGFR1 was the strongest independent predictor of poor outcome.³⁸
• Inhibition of FGFR may have clinical utility in cancers that overexpress FGFRs, such as breast cancer,³⁸ or display a prevalence of FGFR mutations, such as bladder cancer.⁴³ FGF/FGFR signaling may also serve as an escape pathway in tumors that are being treated with inhibitors of other cellular signaling components, such as VEGFR. More recently FGFR1 amplification was found in up to 20% of squamous lung cancers⁴⁴ and may represent the first identified target in smoking-related lung cancer.⁴⁵ Furthermore, their link to cancer dependence has been preclinically established.^37,46
• Dovitinib, orally bioavailable, has demonstrated inhibition of VEGFR and FGFRs in clinical trials.⁴⁷
• BGJ398 is an orally bioavailable, selective inhibitor of the FGFRs at nanomolar concentrations in enzymatic assays and proliferative assays, and in in vivo models.³⁷
• Dovitinib is in Phase III development in renal cell carcinoma, and in Phase II development in advanced breast cancer, hepatocellular carcinoma, and endometrial cancer. A Phase I study with BGJ398 in advanced solid tumors is ongoing.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

BHQ880

A fully human, anti-dickkopf-1 (DKK-1) neutralizing antibody

• The Wnt pathway is a major regulator of mesenchymal stem cell (MSC) differentiation into osteoblasts as well as an important survival factor for active osteoblasts.⁴⁹
• DKK-1 is a soluble Wnt pathway antagonist expressed predominantly in adult bone and upregulated in myeloma patients with osteolytic lesions.⁴⁹
• Overexpression of DKK-1 by myeloma cells may upset the normal balance between osteoblasts and osteoclasts by blocking osteoblast differentiation and turning off anabolic bone formation, thus promoting bone resorption.⁴⁹
• Certain antitumor treatments used for myeloma, such as dexamethasone, have been reported to upregulate DKK-1.⁵⁰
• Agents targeting DKK-1 may play a role in preventing osteolytic bone disease in MM patients.⁵¹
• BHQ880 is a fully human, anti-DKK-1 neutralizing antibody.⁵¹
• BHQ880 is currently in Phase I/II clinical trials in MM.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LFA102

A selective anti-prolactin receptor (PRLR) monoclonal antibody

• PRLR is a member of the class I cytokine receptor family (single transmembrane domain) and mediates the physiological effects of the polypeptide hormone prolactin (PRL).
• PRLR has no intrinsic kinase activity but activates signaling through the JAK-STAT, PI3K-AKT and MEK-ERK1/2 pathways⁵² leading to cell proliferation and survival.
• High circulating levels of PRL have been correlated with increased breast cancer risk in humans, and genetic experiments in mice have demonstrated a causative link between PRL expression and the development of breast and prostate tumors.^53-55
• LFA102* is a humanized monoclonal antibody of the IgG1 kappa subtype. This antibody binds to the putative dimerization region of PRLR in a non-ligand competitive manner and inhibits PRL-induced signaling.⁵⁶
• Preclinical studies suggest multiple potential in vivo mechanisms of action for LFA102: inhibition of PRLR signaling, induction of ADCC, and inhibition of tumor angiogenesis.⁵⁶
• LFA102 is currently in a Phase I study in patients with PRLR-positive castration-resistant prostate cancer or PRLR positive metastatic breast cancer.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

^*Subject to an agreement between Novartis Oncology and Xoma.

LFA102 is subject to an agreement between Novartis Oncology and Xoma.

BEZ235

Buparlisib
(BKM120)

BYL719

Inhibiting tumor proliferation and survival by blocking the PI3K pathway

• PI3K and mTOR are important components of an intracellular signaling network, the PI3K-AKT-mTOR pathway, which regulates cellular metabolism, proliferation, and survival.⁶
• Abnormal activation of the PI3K-AKT-mTOR pathway has been validated as an important step towards the initiation and maintenance of human tumors by epidemiological and preclinical studies.⁶ This signaling cascade is also a key regulator of angiogenesis and upregulated metabolic activities in tumor cells.⁶
• Targeting the PI3K-AKT-mTOR pathway could arrest tumor growth and induce cell death in cancers that are resistant to currently available therapies.^57-59
• BEZ235, BKM120, and BYL719 are oral, targeted anticancer agents in clinical trials. BEZ235 is a PI3K/mTOR dual inhibitor;⁶⁰ BKM120 is a pan-PI3K inhibitor;⁶¹ and BYL719 selectively inhibits PI3Ka. These compounds have shown cell growth inhibition and induction of apoptosis in a variety of tumor cell lines as well as in animal models.^61-63 In addition, in preclinical models they have been shown to possess antiangiogenic properties.^64,65 BEZ235 and BKM120 are currently being investigated in Phase I and II clinical trials in advanced solid tumor patients as a single agent as well as in combination with other agents. Several late-stage trials will be initiated in 2012. A single agent first-in-human study of BYL719 in advanced solid tumor patients is also ongoing.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

AUY922

• HSPs are molecular chaperones that assist in the structural formation and folding of a wide variety of oncogenic client proteins, such as human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), N-RAS, AKT, platelet-derived growth factor receptor (PDGFR), and B-RAF.⁶⁶ When folded incorrectly, these proteins become subject to ubiquitination and proteasomal degradation.
• HSP90 is the most abundant molecular chaperone and is essential for cell survival, proliferation, and apoptosis.⁷ It is an important target for cancer therapeutics because tumor cells, especially those with mutations, exist in a stressful environment and depend on HSP90 to grow and survive. HSP90 inhibitors thus have strong therapeutic potential in a wide variety of tumor types.⁷
• AUY922 is a novel, non-geldanamycin derivative HSP90 inhibitor. Both in vitro and in vivo models demonstrated antitumor activity in a wide range of mutated and wild-type cancer cell lines, primary tumor cells and animal models of cancer, including gastric cancer, NSCLC, hepatocellular cancer, sarcoma, and breast cancer.^7,37
• Phase II studies with AUY922 in NSCLC, breast cancer and gastric cancer are ongoing.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LDE225

LEQ506

Oral, selective inhibitors of smoothened (Smo) receptors

• Smo is a GPCR-like (G protein-coupled receptor) molecule that positively regulates Hh signal transduction, a signaling pathway that plays a critical role in the development and homeostasis of many organs and tissues.⁹
• The Hh pathway is inactive in the absence of ligands as Smo is inhibited by the receptor Patched (Ptch). When Ptch is bound by one of the Hh family of ligands, such as Sonic Hh (SHh), Desert Hh (DHh), and Indian Hh (IHh), activation occurs.⁹
• Genetic activation of the Hh pathway at or upstream of Smo is linked to tumorigenesis of several cancers.⁹
• LDE225 is a selective, orally bioavailable Smo antagonist that has been shown to inhibit Hh- and Smo-dependent proliferation in vivo.³⁷
• LDE225 is currently in a Phase II trial in advanced basal cell carcinoma and in a Phase I trial in medulloblastoma. Additional trials are also planned in other solid tumors.
• LEQ506 is currently being investigated in a Phase I trial in patients with advanced solid tumors.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

INC280
(INCB028060)

Oral, highly selective c-Met receptor tyrosine kinase (RTK) inhibitor

• The hepatocyte growth factor (HGF)-c-Met pathway is one of the most frequently dysregulated pathways in human cancers. Aberrant HGF-c-Met signaling has been documented in a wide range of human malignancies.⁶⁷
• The c-Met pathway can be activated by abnormal HGF and c-Met expression levels, c-Met activating mutations and gene amplifications.⁶⁷
• INC280* is a highly selective small molecule c-Met inhibitor in development for the treatment of solid tumors with activation of the c-Met pathway.⁶⁸
• Exploratory clinical studies in other solid tumors are ongoing.

INC280 (also known in INCB028060) is licensed from Incyte.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

INC280 is licensed from Incyte Corp.

MIDOSTAURIN
(PKC412)

Inhibiting multiple signal transduction pathways

• PKC412 (midostaurin) is an oral multi-targeted kinase inhibitor. In murine models it is an inhibitor of a spectrum of FLT-3 RTK mutants. FLT-3 is mutated in approximately one-third of patients with acute myeloid leukemia (AML)⁶⁹ and is associated with poor prognosis.
• It is an inhibitor of c-KIT, which is mutated in 80% of patients with aggressive systemic mastocytosis (ASM).^70,71
• In in vivo and in vitro studies PKC412 inhibited multiple molecular targets including VEGFR-2, PDGFR, and the Pgp-mediated multidrug resistance gene MDR.⁷¹ In addition, PKC412 inhibits multiple isoforms of the serine/ threonine PKC.
• PKC412 is currently being investigated in newly diagnosed AML with FLT-3 mutations and ASM/mast cell leukemia.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

MIDOSTAURIN
(PKC412)

Inhibiting multiple signal transduction pathways

• PKC412 (midostaurin) is an oral multi-targeted kinase inhibitor. In murine models it is an inhibitor of a spectrum of FLT-3 RTK mutants. FLT-3 is mutated in approximately one-third of patients with acute myeloid leukemia (AML)⁷¹ and is associated with poor prognosis.
• It is an inhibitor of c-KIT, which is mutated in 80% of patients with aggressive systemic mastocytosis (ASM).^72,73
• In in vivo and in vitro studies PKC412 inhibited multiple molecular targets including VEGFR-2, PDGFR, and the Pgp-mediated multidrug resistance gene MDR.⁷³ In addition, PKC412 inhibits multiple isoforms of the serine/ threonine PKC.
• PKC412 is currently being investigated in newly diagnosed AML with FLT-3 mutations and ASM/mast cell leukemia.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LCL161

Promoting cancer cell death by deactivating inhibitor of apoptosis proteins (IAPs)

• IAPs shield cancer cells from cell death by inhibiting caspases¹¹ - the enzymes that mediate apoptosis - and by regulating cancer-relevant signaling molecules.¹²
• Normally, the ability of IAPs to buffer an apoptotic signal is subject to regulation by Smac, a mitochondrial protein that binds to IAPs, disengaging them from caspases and, in the case of cIAP1 and cIAP2, facilitating their proteosome-mediated destruction.⁷²
• In in vitro studies LCL161 is a mimetic of Smac that binds to IAPs with high affinity and initiates the destruction of cIAP1 and cIAP2. LCL161 kills tumor cells by neutralizing this shield used by cancer to evade cell death and indirectly activating caspases.³⁷
• In preclinical studies, LCL161 demonstrated antitumor activity both as a single agent and in combination with chemotherapy against a range of solid tumors including primary models of triple negative breast cancer.³⁷
• A Phase I study in advanced solid tumors in combination with paclitaxel is currently ongoing.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LCI699

PANOBINOSTAT
(LBH589)

Pan-DAC inhibitor - targeting epigenetic and multiple oncogenic pathways

• DAC enzymes regulate transcription and other cellular processes by removing acetyl groups from target proteins.¹⁵ A target protein associated with DAC is the histone, the core protein around which DNA is wrapped.^73-76 DAC activity is associated with DNA modifications that lead to increased growth and proliferation of cancer cells. The second major target for DACs are non-histone proteins, which have been shown to modulate cancer cell growth and survival pathways.^74,77
• In preclinical studies pan-DACi have been shown to have multiple effects in tumor cell lines: decreased oncoprotein expression (e.g. Bcr-Abl, HER2), decreased angiogenesis, induction of apoptosis, induction of cell cycle arrest, and decreased tumor cell motility and invasion.⁷³
• Panobinostat (LBH589) is a pan-DACi being studied in many hematologic malignancies, including MM, myelodysplastic syndromes (MDS), and myelofibrosis.^73,78
• Phase I/II studies are evaluating panobinostat in multiple combinations with chemotherapy and/or targeted therapy in MM, MDS, myelofibrosis, and other hematologic malignancies.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LDK378

Oral, highly selective anaplastic lymphoma kinase (ALK) inhibitor

• ALK, a protein tyrosine kinase gene, was first described in ALCL, where a t(2;5)(p23;q35) chromosomal translocation resulted in fusion of the nucleolar phosphoprotein gene NPM on chromosome 5 (5q35) to the previously unidentified ALK gene on chromosome 2 (2p23).²⁰ ALK translocations involving a variety of other partner genes have subsequently been described in several other malignancies, including NSCLC and IMT.^21,22
• In NSCLC cells, ALK typically forms a fusion gene with the echinoderm microtubule-associated protein-like 4 (EML4) to create EML4-ALK.^22,23,89 EML4-ALK was also recently identified in a small proportion of breast and colorectal tumors.²³ A second fusion transcript KIF5B-ALK has also recently been reported in NSCLC.⁹⁰
• EML4-ALK is an oncogenic driver in cellular and animal models, and inhibition of ALK induces apoptosis of EML4-ALK-containing cell lines in vitro and in vivo.^24,25
• LDK378 is an adenosine triphosphate (ATP)-competitive inhibitor of ALK.³⁷
• LDK378 is an orally bioavailable, selective, small molecule inhibitor of ALK, which has entered Phase I investigation.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LGH447

Highly selective, oral pan-PIM inhibitor

• The PIM family consists of three serine/threonine protein kinases (PIM1-3) which play a role in cell cycle progression, cell survival, and tumorogenesis.^26,91 Elevated c-Myc levels are commonly associated with PIM overexpression in cancer, and they act synergistically in carcinogenesis.^26,92
• In normal hematologic cells, PIM1 and PIM2 are expressed in response to multiple cytokines, chemokines, and growth factors.^27,91 Binding of these factors to their receptors leads to transcriptional activation of PIM genes via activation of the JAK-STAT signaling pathway.²⁶
• Elevated levels of PIM1 and PIM2 are common in cancer tissue samples from patients with several hematologic malignancies.^26,27 In addition, overexpression of PIM1 in prostate and pancreatic cancers, increased expression of PIM2 in liver cancer, as well as increased PIM3 in various solid tumors, have been reported.^26,27
• LGH447 is a selective, orally bioavailable, small molecule pan-PIM kinase inhibitor.
• In vivo, LGH447 demonstrated activity in xenograft models of MM, AML, and B-cell NHL.³⁷
• LGH447 is currently under Phase I development for the treatment of hematologic malignancies and solid tumors.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

LGK974

Small molecule inhibitor of Porcupine

• The Wnt pathway regulates cellular proliferation, migration, morphology, apoptosis, differentiation, and stem cell self-renewal.^29,30 Dysregulation of the Wnt pathway is known to play a critical role in the development of a variety of malignancies, including melanoma, breast cancer, and squamous cell carcinoma.^29,30,93
• Interaction between Wnt ligands and the co-receptors Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) initiates the canonical Wnt pathway. Activation of this pathway prevents proteosomal degradation of ß-catenin.²⁹ ß-catenin translocates to the nucleus where it interacts with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to activate specific Wnt-target genes.²⁹
• Wnt ligands require post-translational palmitoylation in order to be secreted and functionally active.^28,94 The key enzyme regulating this process is Porcupine, a membrane bound O-acyltransferase enzyme, required and specific for palmitoylation of Wnt ligands.^28,94
• LGK974 is a selective and orally bioavailable Porcupine inhibitor under development for the treatment of cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner.³⁷
• A Phase I study of LGK974 in patients with melanoma or lobular breast cancer is currently ongoing.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

CTL019
(CART-19)

Chimeric antigen receptor-transduced T cells targeted to CD19

• CD19 is widely expressed on B cells, starting from the earliest precursor cells through all stages of maturation.⁹⁹
• CTL019 therapy involves adoptive transfer of autologous T cells that have been modified to express chimeric antigen receptors designed to recognize and kill CD19+ cancer cells.^100,101
• The chimeric antigen receptor consists of an intracellular T-cell receptor CD3-zeta chain signaling domain that induces T-cell activation, a costimulatory 4-1BB domain that enhances T-cell mediated responses and anti-CD19 antibody fragments that bind to CD19.^102-104
• T cells harvested from a patient are transduced with a lentiviral vector encoding the anti-CD19 chimeric antigen receptor. The resulting CTL019 cells are expanded ex vivo prior to infusion into the patient, who has undergone lymphocyte-depleting therapy. The CTL019 cells destroy tumor cells expressing CD19 and remain persistent in the body to guard against residual or recurring disease.¹⁰¹
• Ongoing pilot studies are investigating the activity and safety of CTL019 therapy in patients with resistant or refractory CD19+ hematologic malignancies. Preliminary data from 3 patients with CLL have been published.^100,101,104

CTL019 (also known as CART-19) is licensed from the University of Pennsylvania (Penn) and subject to the agreement between Novartis and Penn.

CTL019 is investigational. Efficacy and safety have not been established. There is no guarantee that it will become commercially available.

Deferasirox

Everolimus

CTL019 (also known as CART-19) is licensed from the University of Pennsylvania (Penn) and subject to the agreement between Novartis and Penn.

Everolimus

Everolimus

Pasireotide LAR

Ruxolitinib
(NC424)

Also known as INC424 (INCB018424), is being developed collaboratively by Incyte and Novartis AG. Novartis AG has licensed the rights to INC424 outside the United States. Incyte maintains the rights within the United States. Phase II trial conducted by Incyte (NCT00726232)

LJM716

VAY736